Ghrelin promotes thymopoiesis during aging
Vishwa Deep Dixit, … , Roy G. Smith, Dennis D. Taub
Vishwa Deep Dixit, … , Roy G. Smith, Dennis D. Taub
Published October 1, 2007
Citation Information: J Clin Invest. 2007;117(10):2778-2790. https://doi.org/10.1172/JCI30248.
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Research Article Immunology

Ghrelin promotes thymopoiesis during aging

Abstract

The decline in adaptive immunity, T lymphocyte output, and the contraction of the TCR repertoire with age is largely attributable to thymic involution. The loss of thymic function with age may be due to diminished numbers of progenitors and the loss of critical cytokines and hormones from the thymic microenvironment. We have previously demonstrated that the orexigenic hormone ghrelin is expressed by immune cells and regulates T cell activation and inflammation. Here we report that ghrelin and ghrelin receptor expression within the thymus diminished with progressive aging. Infusion of ghrelin into 14-month-old mice significantly improved the age-associated changes in thymic architecture and thymocyte numbers, increasing recent thymic emigrants and improving TCR diversity of peripheral T cell subsets. Ghrelin-induced thymopoiesis during aging was associated with enhanced early thymocyte progenitors and bone marrow–derived Lin–Sca1+cKit+ cells, while ghrelin- and growth hormone secretagogue receptor–deficient (GHS-R–deficient) mice displayed enhanced age-associated thymic involution. Leptin also enhanced thymopoiesis in aged but not young mice. Our findings demonstrate what we believe to be a novel role for ghrelin and its receptor in thymic biology and suggest a possible therapeutic benefit of harnessing this pathway in the reconstitution of thymic function in immunocompromised subjects.

Authors

Vishwa Deep Dixit, Hyunwon Yang, Yuxiang Sun, Ashani T. Weeraratna, Yun-Hee Youm, Roy G. Smith, Dennis D. Taub

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Figure 3

Ghrelin enhances thymic size and cellularity in aging mice.

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Ghrelin enhances thymic size and cellularity in aging mice. (A) Ghrelin ...
(A) Ghrelin infusion for 2 weeks via s.c. osmotic pumps caused a significant increase in thymic size in 14-month-old animals. (B) Ghrelin did not alter thymocyte counts in the 2-month-old mice but significantly increased total thymocyte numbers in 14-, 20- and 24-month-old mice. (C–E) Ghrelin treatment significantly increased body weight in 14-month-old mice (C) without a significant change the peripheral IGF-1 (D) or leptin (E) levels. *P < 0.05. (F) Ghrelin infusion into 14-month-old mice led to increased GHS-R expression (green) with partial colocalization with CD11c+ cells. In addition, ghrelin administration resulted in an enhanced number of CD11c+ dendritic cells in the thymic medulla. (G–J) Compared with 14-month-old vehicle-infused animals, ghrelin infusion significantly improved the thymic architecture. Ghrelin infusion is associated with increased cellularity, clear delineation (arrowheads) of cortex (dark stain) from medulla (light stain) and well defined CMJ (dotted line), the site where progenitors arrive in thymus. (K and L) Frozen thymi from 14-month-old mice stained for Oil Red O displayed an increased number of “adipocyte-like” lipid-laden cells (arrowheads) in the parenchyma and perivascular space, while in ghrelin-infused mice, a marked reduction in PVS (K and L) with reduced numbers of lipid droplet–containing cells (L). Original magnification, ×5 (G and H); ×10 (F, I, and J); ×20 (K and L).